Somatically mutated regions of immunoglobulin on human b-cell lymphomas code for peptides that bind to autologous major histocompatibility complex class I, providing a potential target for cytotoxic T cells

• Published in: Cancer research (Chicago, Ill.) Vol. 61; no. 13; pp. 5145 - 5152
• Main Authors: GRICKS, Clair S, RAWLINGS, Eira, FORONI, Letizia, MADRIGAL, J. Alejandro, AMLOT, Peter L
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01-07-2001
• Subjects: Amino Acid Sequence; Antineoplastic agents; Binding, Competitive; Biological and medical sciences; Cell Line; Epitopes, T-Lymphocyte - genetics; Epitopes, T-Lymphocyte - immunology; histocompatibility antigen HLA; HLA-A Antigens - immunology; HLA-A Antigens - metabolism; Humans; Immunoglobulin Idiotypes - genetics; Immunoglobulin Idiotypes - immunology; Immunotherapy; Interferon-gamma - biosynthesis; Interferon-gamma - secretion; Lymphocyte Activation - immunology; Lymphoma, B-Cell - genetics; Lymphoma, B-Cell - immunology; Medical sciences; Mutation; Oligopeptides - genetics; Oligopeptides - immunology; Oligopeptides - metabolism; Peptide Library; Pharmacology. Drug treatments; Reverse Transcriptase Polymerase Chain Reaction; T-Lymphocytes, Cytotoxic - immunology; Antineoplastic agent; HLA-System; Peptides; Gene product; Major histocompatibility system; Tumoral tissue; Somatic mutation; Target; Binding capacity; Lymphoproliferative syndrome; T-Lymphocyte; Malignant lymphoma; Cytotoxic T lymphocyte; Class I histocompatibility antigen; Human; Immunoglobulins; Immune response; Nucleotide sequence; Malignant hemopathy; B-Lymphocyte; Autologous system; Lymphoid tissue; Gene expression; In vitro; DNA; Genome; Molecular domain; Idiotype
• ISSN: 0008-5472; 1538-7445

Lymphoma-derived immunoglobulin idiotype (Id) is a well-characterized, tumor-specific antigen on B-cell malignancies. Immunotherapy using lymphoma immunoglobulin can lead to clinical responses mostly associated with anti-Id antibody. We cloned the Id from B-cell lymphomas, sequenced them, and used bioinformatics to select autologous MHC class I binding peptides from somatically mutated regions of the lymphoma Id. Peptides from patients who were HLA-A1, HLA-A2, HLA-A3, or HLA-A11 positive were analyzed in the T2 stabilization assay and a competitive peptide-binding assay. By both methods, approximately half of the peptides analyzed, regardless of HLA type, bound with intermediate or high affinity. Peptide binding affinity was similar to viral peptide sequences known to provide targets for cytotoxic T cells. Further investigation of lymphocyte responses to stimulation by autologous Id peptides versus Id peptides from other patients revealed that three of five patients in complete remission or with low volume, stable disease responded to self-peptides by IFN-gamma secretion greater than that seen with non-self peptides, whereas none of five patients with progressive disease responded to their own lymphoma Id. We have shown that mutated regions of lymphoma Id contain MHC class I binding peptides that are potential targets for cytotoxic T cells. Immunotherapy using the tumor-specific mutated regions from lymphoma Id avoids the need to break innate tolerance toward the germ-line protein sequences present on normal and malignant B cells.